Formoterol, N-[2-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl) amino)ethyl)phenyl]formamide, particularly in the form of its fumarate salt, is a bronchodilator used in the treatment of inflammatory or obstructive airways diseases.
EP 057 401 and U.S. Pat. No. 4,472,393 describe mometasone i.e. 9,21-dichloro-11,17dihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione, esters thereof such as mometasone furoate i.e. (11 beta, 16alpha)-9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methylpregna-1,4-diene-3,20-dione, and pharmaceutical formulations thereof. Mometasone is an antiinflammatory corticosteroid, which is now used clinically in the treatment of respiratory disorders.
WO 00/51591 describes medicaments and pharmaceutical compositions containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or a solvate of said salt and (B) mometasone furoate, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease. As an example for a suspension aerosol formulation for a metered dose inhaler, WO 00/51591 discloses a composition consisting of 0.012% by weight formoterol fumarate dihydrate, 0.250% by weight mometasone furoate, 2.5% by weight ethanol, 60.768% by weight 1,1,1,2,3,3,3-heptafluoropropane (HFC 227) and 36.740% by weight 1,1,1,2-tetrafluoroethane (HFC 134a).
WO 00/53187 discloses suspension aerosol formulations consisting of micronized formoterol fumarate dihydrate (6 μg), micronized mometasone furoate monohydrate (100 μg), oleic acid (0.005% based on propellant), ethanol (2% based on propellant) and HFC 134a (up to 25, 50 or 100 μl) as well as suspension formulations consisting of micronized formoterol fumarate dihydrate (12 μg), micronized mometasone furoate monohydrate (200 μg), oleic acid (0.01% based on propellant), ethanol (3% based on propellant) and HFC 227/HFC 134a (15/85, up to 25, 50 or 100 μl).
WO 01/78744 discloses suspension aerosol formulations consisting of micronized formoterol fumarate or the dihydrate thereof (6 to 24 μg per actuation), micronized mometasone furoate (100 or 200 μg per actuation) and HFC 134a.
An important aspect in formulating pharmaceutical compositions which have a micronized drug dispersed in a propellant is the homogeneity of the dispersed drug. The drug can sediment or cream depending on the density difference between drug and propellant, or it can flocculate, which requires some degree of agitation to deflocculate it. Inhomogeneity of the dispersed drug may in turn lead to delivery of incorrect doses when the formulation is dispensed from the metering valve. This aspect represents a challenge when formulating suspensions of a single drug, but is particularly challenging for a combination of drugs, like formoterol and mometasone, in which each drug has a significantly different potency and thus concentration in formulation. Furthermore, the densities of the two drugs differ appreciably, e.g. formoterol fumarate has a density of 1.3 g cm−3, while mometasone furoate has a density of 1.4 g cm−3.